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CLINICAL RESEARCH: ANTITHROMBOTIC THERAPY

The Relative Efficacy and Safety of Clopidogrel in Women and Men

A Sex-Specific Collaborative Meta-Analysis

Jeffrey S. Berger, MD^_*,_*, Deepak L. Bhatt, MD, MPH^,, Christopher P. Cannon, MD, Zhengming Chen, MBBS, DPhil, Lixin Jiang, MBBS, MSc^||, James B. Jones, PhD, MBA, Shamir R. Mehta, MD^¶, Marc S. Sabatine, MD, MPH^,#, Steven R. Steinhubl, MD, Eric J. Topol, MD^_** and Peter B. Berger, MD

^_* New York University School of Medicine, New York, New York
VA Boston Healthcare System, Boston, Massachusetts
Brigham and Women's Hospital, Boston, Massachusetts
University of Oxford, Oxford, England
^|| Fuwai Hospital, Chinese Academy of Medical Sciences, Beijing, China
^¶ McMaster University, Hamilton, Ontario, Canada
^# Harvard Medical School, Boston, Massachusetts
^_** Scripps Translational Research Institute, La Jolla, California
Geisinger Clinic, Danville, Pennsylvania

Manuscript received December 2, 2008; revised manuscript received May 11, 2009, accepted May 26, 2009.

^_* Reprint requests and correspondence: Dr. Jeffrey S. Berger, New York University School of Medicine, 530 First Avenue, Skirball 9R, New York, New York 10016 (Email: jeffrey.berger{at}nyumc.org).

	Abstract

Top Abstract Methods Results Discussion Conclusions References

 
Objectives: This study sought to investigate the efficacy and safety of clopidogrel in women and men.

Background: Previous analyses have shown sex-based differences in response to several antiplatelet medications. Little is known about the efficacy and safety of clopidogrel in women and men.

Methods: This study performed a meta-analysis of all blinded randomized clinical trials comparing clopidogrel and placebo (CURE [Clopidogrel in Unstable Angina to Prevent Recurrent Events], CREDO [Clopidogrel for the Reduction of Events During Observation], CLARITY–TIMI 28 [Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis In Myocardial Infarction 28], COMMIT [Clopidogrel and Metoprolol in Myocardial Infarction Trial], and CHARISMA [Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance] trials), involving a total of 79,613 patients, of whom 30% were women. The relative efficacy and safety of clopidogrel at reducing cardiovascular events (cardiovascular death, myocardial infarction [MI], or stroke) in women and men was estimated using random-effects modeling.

Results: Overall, clopidogrel was associated with a highly significant 14% proportional reduction in the risk of cardiovascular events (odds ratio [OR]: 0.86; 95% confidence interval [CI]: 0.80 to 0.93), with no significant differences in treatment effect between women and men. Among the 23,533 women enrolled, there were fewer cardiovascular events in the clopidogrel group compared with the placebo group (11.0% vs. 11.8%; OR: 0.93; 95% CI: 0.86 to 1.01). In women the risk reduction with clopidogrel seemed to be greatest for MI (OR: 0.81; 95% CI: 0.70 to 0.93), with the effects on stroke (OR: 0.91; 95% CI: 0.69 to 1.21) or total death (OR: 0.99; 95% CI: 0.90 to 1.08) not statistically significant. Among the 56,091 men enrolled, there were fewer cardiovascular events in those receiving clopidogrel compared with placebo (7.8% vs. 9.0%; OR: 0.84; 95% CI: 0.78 to 0.91), and the risk reduction was significant for MI (OR: 0.83; 95% CI: 0.76 to 0.92), stroke (OR: 0.83; 95% CI: 0.71 to 0.96), and total death (OR: 0.91; 95% CI: 0.84 to 0.97). Clopidogrel increased the risk of major bleeding in both women (OR: 1.43; 95% CI: 1.15 to 1.79) and men (OR: 1.22; 95% CI: 1.05 to 1.42).

Conclusions: Clopidogrel reduces the risk of cardiovascular events in both women and men.

Key Words: sex • antiplatelet agents • clopidogrel • randomized trial • cardiovascular disease

Abbreviations and Acronyms   ACS = acute coronary syndrome   CI = confidence interval   MI = myocardial infarction   OR = odds ratio

It has been previously shown that the response to aspirin for the primary prevention of cardiovascular disease is different between women and men (9). Although a similar protection from cardiovascular events was noted, women derived most of their benefit from a reduction in the risk of stroke, whereas men derived most of their benefit from a reduction in the risk of myocardial infarction (MI). The response to another antiplatelet medication, glycoprotein IIb/IIIa inhibitors, was shown to have a sex-specific response as well (10). However, there are very few data on the effect of clopidogrel in men versus women, even though it is one of the most frequently prescribed drugs.

Several randomized trials have evaluated the effect of clopidogrel on cardiovascular events across a broad spectrum of coronary disease (14–20). Accordingly, the most recent acute coronary syndrome (ACS) guidelines make clopidogrel treatment a class I recommendation with grade A evidence in several different clinical situations (21–23). Unfortunately, many of the clinical trials did not include an adequate number of women to determine whether the benefits were similar in men and women. Trials that did report results in women reported aggregate events (e.g., major cardiovascular events), but did not report specific outcomes such as death, MI, or stroke separately. Ex vivo assessment of the antiplatelet effect of clopidogrel suggests that women are more likely to be hyporesponsive to clopidogrel than men (24), suggesting a potential clinical difference in the effectiveness of clopidogrel according to sex.

Accordingly, to better understand the impact of sex on the response to clopidogrel, we performed a sex-specific collaborative meta-analysis of clopidogrel therapy for the prevention of cardiovascular events.

	Methods

Top Abstract Methods Results Discussion Conclusions References

 
Literature search.   This meta-analysis considered randomized clinical trials comparing clopidogrel in combination with aspirin to aspirin alone for the treatment of patients at high risk for cardiovascular events. Comprehensive searches of the Medline and Cochrane Central Register of Controlled Trials databases were performed using Internet-based engines (PubMed and OVID) for studies published between 1999 and May 2007. Search terms included clopidogrel, cardiovascular disease, MI, stroke, percutaneous coronary intervention, and randomized controlled trials, as well as combinations of these terms. Experts in the field were questioned, bibliographies of retrieved articles were searched for other relevant studies, and major scientific meetings were monitored.

Study selection.   Trials that met the following criteria were included: 1) prospective, randomized, placebo controlled, open or blinded trials; 2) assignment of participants to clopidogrel treatment and a placebo group; and 3) data on all-cause mortality, cardiovascular death, MI, stroke, and major bleeding. A total of 197 potentially eligible studies were identified, and 131 were excluded based on title and abstract for not fulfilling inclusion criteria on the basis of intervention. On further review, 61 studies were excluded either because of their nonrandomized nature or because they were not placebo controlled (Fig. 1).

View larger version (27K): [in this window] [in a new window] [Download PPT slide]   Figure 1 Flow Diagram of the Trial Selection Process

Statistical analysis.   For this collaborative meta-analysis, the principal investigators of each of the included trials supervised the extraction and verified the accuracy of the data from the databases of each trial. Sex-specific data from each trial, which have not been previously published, were combined for this study. The statistical analysis was performed using Stata Statistical Software, release 10 (StataCorp, College Station, Texas). Data were analyzed according to the intention-to-treat principle. The Cochrane Q statistic was calculated to assess heterogeneity among the trials for both men and women. However, because the lack of heterogeneity does not necessarily imply homogeneity, a summary odds ratio (OR) was calculated using a random-effects model from the ORs and the 95% confidence intervals (CIs) for each end point in each study using Mantel-Haenszel methods. To test for differences between men and women for each end point, we used a formal test for heterogeneity that is based on the Cochrane Q statistic (25). This test evaluates the degree to which overall heterogeneity can be explained by heterogeneity between subgroups (25). If the p value for the test of heterogeneity is significant (p < 0.05), it suggests that the treatment effect differs between groups. In addition, we investigated differences between subgroups using metaregression to explore the relationship between sex and the pooled value for each outcome measure. The results were nearly identical for each outcome.

The statistical rationale for combining the data has been previously described and used extensively (26). Briefly, the basic principle is that patients allocated to an intervention in a specific trial are only compared with those allocated to the control treatment in the same trial, avoiding direct comparisons of patients across different trials with different designs and lengths of follow-up. These methods provide for combination of information from multiple 2 x 2 tables, generating a summary OR and its 95% CI as reviewed by Mantel and Haenszel (27) and modified by Yusuf et al. (28). The data were also analyzed using a random-effects model to generate relative risks and 95% CIs. These results did not qualitatively differ from the primary analysis. A value of p < 0.05 was judged as statistically significant. Sensitivity analyses were performed for each outcome to assess the contribution of each study to the pooled estimate by excluding individual trials one at a time and recalculating the combined OR for the remaining studies. To assess publication bias, we generated a funnel plot of the logarithm of effect size and compared it with the SE for each trial.

	Results

Top Abstract Methods Results Discussion Conclusions References

 
Search results.   We identified 5 randomized controlled trials for inclusion (16–20). Women constituted between 20% and 39% of patients enrolled in the trials. In total, 79,613 individuals were enrolled in the 5 trials, of whom 23,522 (30%) were women.

Details of the included studies are shown in Table 1. A broad spectrum of cardiovascular disease was represented by the 5 trials. The CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial (20) enrolled patients with a non–ST-segment elevation ACS, whereas the CLARITY–TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis In Myocardial Infarction 28) (18) and COMMIT (17) trials enrolled patients with an ST-segment elevation MI. The CREDO (Clopidogrel for the Reduction of Events During Observation) (19) trial enrolled patients in whom a percutaneous coronary intervention was planned. Two-thirds of the patients in the CREDO study had a diagnosis of unstable angina or had suffered a recent MI. The CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) (16) trial enrolled both patients with established vascular disease (80%) and patients with multiple risk factors for but without documented vascular disease (20%). The weighted mean duration of follow-up was 8.3 months. Baseline characteristics of the individuals are presented in Table 2.

Major cardiovascular events.   A total of 2,680 major cardiovascular events occurred among the 23,533 women enrolled in these trials (Fig. 2), with the event rate being nonsignificantly lower in women allocated clopidogrel compared with those allocated placebo (11.0% vs. 11.8%; OR: 0.93; 95% CI: 0.86 to 1.01).

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Figure 2 Effect of Clopidogrel Treatment on the Effect of Major Cardiovascular Events Major cardiovascular events are defined as the composite of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death. Pooled ORs are from a random-effects model. Sizes of data markers are proportional to the amount of data contributed by each trial. CHARISMA = Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance; CI = confidence interval; CLARITY–TIMI 28 = Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis In Myocardial Infarction 28; COMMIT = Clopidogrel and Metoprolol in Myocardial Infarction Trial; CREDO = Clopidogrel for the Reduction of Events During Observation; CURE = Clopidogrel in Unstable Angina to Prevent Recurrent Events; OR = odds ratio.

Mortality.   Overall, there were 2,069 deaths in 23,522 women (Fig. 3), and this risk was not significantly reduced by allocation to clopidogrel in women (8.7% vs. 8.8%; OR: 0.99; 95% CI: 0.90 to 1.08). Mode of mortality was analyzed in 4 of the 5 trials; no association was noted between clopidogrel allocation and cardiovascular mortality (OR: 1.04; 95% CI: 0.86 to 1.25).

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Figure 3 Effect of Clopidogrel Treatment on the Effect of All-Cause Mortality Pooled ORs are from a random-effects model. Sizes of data markers are proportional to the amount of data contributed by each trial. Abbreviations as in Figure 2.

MI.   There were 766 MIs reported among the 23,533 women (Fig. 4), with the rate being 2.9% in women allocated clopidogrel compared with 3.6% in women allocated placebo (OR: 0.81; 95% CI: 0.70 to 0.93). Each trial reported a decreased risk of MI associated with clopidogrel treatment when analyzed separately.

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Figure 4 Effect of Clopidogrel Treatment on the Effect of Myocardial Infarction Pooled ORs are from a random-effects model. Sizes of data markers are proportional to the amount of data contributed by each trial. Abbreviations as in Figure 2.

Stroke.   A total of 399 strokes occurred among women in the 5 trials (Fig. 5), and the 9% proportional risk reduction for total stoke with clopidogrel was not statistically significant (1.6% vs. 1.9%; OR: 0.91; 95% CI: 0.69 to 1.21), nor were the separate effects of clopidogrel on ischemic stroke (OR: 0.89; 95% CI: 0.71 to 1.12) or hemorrhagic stroke (1.2% vs. 1.4%; OR: 0.82; 95% CI: 0.29 to 2.32) among women.

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Figure 5 Effect of Clopidogrel Treatment on the Effect of Stroke Pooled ORs are from a random-effects model. Sizes of data markers are proportional to the amount of data contributed by each trial. Abbreviations as in Figure 2.

Major bleeding.   A total of 333 major bleeding events occurred among women (Fig. 6), with the odds being significantly higher among women allocated clopidogrel than among those allocated placebo (1.7% vs. 1.2%; OR: 1.43; 95% CI: 1.15 to 1.79). Each trial reported an increased risk of major bleeding associated with clopidogrel treatment.

View larger version (18K): [in this window] [in a new window] [Download PPT slide]   Figure 6 Effect of Clopidogrel Treatment on the Effect of Major Bleeding Pooled ORs are from a random-effects model. Sizes of data markers are proportional to the amount of data contributed by each trial. Abbreviations as in Figure 2.

Subgroup analysis.   When patients enrolled with an ACS (the CURE, COMMIT, and CLARITY–TIMI 28 trials) are analyzed separately, the efficacy and safety profile in women and men were similar to the results seen in the entire study population (Table 3). In the CHARISMA trial, clopidogrel was associated with an increase in adverse events (including death when analyzed separately) among patients without established cardiovascular disease. We therefore excluded these patients (n = 3,449) and evaluated the benefit and risk of clopidogrel only among those with established cardiovascular disease in the CHARISMA trial and the other 4 trials (Table 3). Once again, the efficacy and safety profile in women and men is similar to the results seen in the entire population.

	Discussion

Top Abstract Methods Results Discussion Conclusions References

 
In this large study comparing the efficacy and safety of clopidogrel versus placebo between women and men, we show that clopidogrel reduced the risk of major cardiovascular events in both women and men. In women, the overall effect of clopidogrel was driven by a reduction of MI. In men, however, the effects of clopidogrel on MI, stroke, and all-cause mortality were separately significant. Despite these observations, there was no evidence of statistically significant heterogeneity when the effect of clopidogrel was compared between women and men, indicating that much of the difference between men and women could be explained by play of chance. Regarding major bleeding, there were small but real excess risks with clopidogrel therapy in both men and women.

Benefit of clopidogrel therapy.   Platelet inhibition remains a key component in the prevention and treatment of ischemic heart disease (6–8). Treatment with aspirin has been shown to reduce cardiovascular morbidity and mortality in a wide variety of patients and clinical settings (29). Large, randomized trials have shown improved outcomes when clopidogrel is added to aspirin across the spectrum of cardiovascular disease (16–20). In a previous meta-analysis (30), clopidogrel was found to decrease cardiovascular morbidity and mortality. However, there had not previously been a specific analysis of the efficacy and safety of clopidogrel in women compared with men.

In this pooled sex-specific analysis, we found that clopidogrel confers benefit in both women and men. We noted an absolute risk reduction of 0.8% and 0.7% in women for the composite end point and for MI alone, respectively. In other words, an average duration of 8.3 months of treatment with clopidogrel results in an absolute benefit of approximately 8 cardiovascular events and 7 MIs prevented per 1,000 women treated. Among women with ACS, we found an absolute risk reduction of 0.9% in women for the composite end point, corresponding to 9 fewer cardiovascular events per 1,000 women treated with clopidogrel. For men, the absolute risk reduction for the composite and MI end point was 1.2% and 0.6%, respectively, corresponding to approximately 12 fewer cardiovascular events and 6 fewer MIs prevented per 1,000 men treated for an average of 8.3 months. Among men with ACS, we found an absolute risk reduction of 1.3% in men for the composite end point, corresponding to 13 fewer cardiovascular events per 1,000 men treated with clopidogrel.

Safety of clopidogrel therapy.   Although effective in preventing further thrombotic events, clopidogrel increases the risk of bleeding. Adding clopidogrel to aspirin therapy resulted in a 43% and 21% increased risk of major bleeding in women and men, respectively. Based on the absolute increase in bleeding of 0.5% and 0.2% in women and men, respectively, the number needed to cause 1 major bleeding event (from an average treatment duration of 8.3 months) with clopidogrel was 200 women and 500 men. In other words, clopidogrel treatment over an average period of 8.3 months results in an absolute increase of approximately 5 major bleeding events per 1,000 women and 2 major bleeding events per 1,000 men. Among those with ACS, in whom the bleeding risk is believed to be higher, the absolute increase in major bleeding remained 0.5% for women and 0.14% in men.

To better evaluate the balance of benefit versus risk in both groups, we provide the number needed to treat for each individual end point and for a net clinical end point (MI, stroke, cardiovascular death, or major bleeding) in Table 4. Despite no significant difference between women and men, there seems to be a greater benefit for clopidogrel in men. To obtain net clinical benefit over a weighted mean follow-up of 8.3 months, one needed to treat 101 men and 435 women.

Clopidogrel, a nonreversible platelet antagonist, is a second-generation drug in the class of thienopyridines (35). Although clopidogrel is a more potent antiplatelet agent than aspirin, both drugs have wide ranges of platelet inhibition (36). Several studies have noted increased rates of clinical events among those with decreased platelet inhibition (hyporesponsiveness) to aspirin or clopidogrel (36–42). In response, much attention is focused on identification of these groups with aspirin or clopidogrel hyporesponsiveness. As has been reported with aspirin (43–45), women are also more often found to be hyporesponsive to clopidogrel (24). However, the clinical implication of these findings is uncertain.

The current study shows that both women and men benefit from clopidogrel across a wide spectrum of vascular disease and clinical presentations. The lack of significant heterogeneity between women and men in their response to clopidogrel for the primary end point and each individual component reinforces this finding. Furthermore, both women and men are at risk for major bleeding from clopidogrel when compared with placebo. Consistent with prior studies (46–49), a numerically increased risk of major bleeding was found among women compared with men; nevertheless, no statistically significant difference existed between the sexes. However, with a greater emphasis being placed on bleeding and its consequences (50), this finding is important and may affect future drug development.

Study limitations.   First, as in most meta-analyses, these results should be incorporated with caution because the initial loading dose of clopidogrel and duration of treatment were not uniform. Importantly, these differences did not result in any statistically significant differences in the size of the treatment effect between the trials. Furthermore, after removal of the largest trial with the shortest duration of follow-up (the COMMIT trial), the results obtained were nearly identical. Second, we were unable to determine what effect clopidogrel has on particular subgroups of interest. Only an analysis of patient-level data from all of the trials would allow an examination of the benefits of clopidogrel in particular subgroups. Third, among the 5 trials, 4 different definitions of major bleeding were used. Although this should not change the conclusion of the results, these variations in major bleeding definitions make it impossible to determine the true frequency of bleeding using any one of the definitions. Fourth, although no significant differences in benefit or risk from clopidogrel between men and women were observed on heterogeneity analyses, the benefit and risk of clopidogrel was not perfectly homogenous in women and men, and we are unable to rule out with certainty that some difference in benefit and risk might exist. Finally, meta-analysis remains retrospective research that is subject to the methodological deficiencies of the included studies. We minimized the likelihood of bias by developing a detailed protocol before initiating the study, by performing a meticulous search for published and unpublished studies, and by using explicit methods for study selection, data extraction, and data analysis.

	Conclusions

Top Abstract Methods Results Discussion Conclusions References

 
This meta-analysis of more than 23,000 women and 56,000 men shows that clopidogrel is effective in reducing cardiovascular events, and this difference is not significantly different between women and men. Whereas women derived a majority of their cardiovascular benefit by reducing the risk of MI, men had a significant reduction in the risk of MI, stroke, and all-cause mortality. This benefit was consistent across the spectrum of patients with cardiovascular disease and did not differ by clinical presentation.

	Footnotes

 
This was an investigator-initiated study, and was supported by American Heart Association Fellow to Faculty Award 0775074. Dr. Berger has received research support (<$10,000) from AstraZeneca. Dr. Bhatt is a consultant for Arena, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardax, Centocor, Daiichi-Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, McNeil, Medtronic, Millennium, Molecular Insights, Otsuka, ParinGenix, PDL Biopharma, Philips, Portola, Sanofi, Schering, Takeda, The Medicines Company, and Vertex, and has received research grants from Bristol-Myers Squibb, Eisai, Ethicon, Heartscape, Sanofi-Aventis, and The Medicines Company. Dr. Cannon has received research grants/support from Accumetrics, AstraZeneca, Bristol-Myers Squibb/Sanofi Partnership, GlaxoSmithKline, Intekrin Therapeutics, Merck, Merck/Schering-Plough Partnership, Novartis, and Takeda, and serves as Clinical Advisor and has equity in Automedics Medical Systems. Dr. Chen has received research grants from AstraZeneca and Merck. Dr. Jones has received unrestricted research grants from Merck, GlaxoSmithKline, Roche, DSI, Takeda, and AstraZeneca. Dr. Mehta has received institutional research grant support from Sanofi-Aventis, Bristol-Myers Squibb, and GlaxoSmithKline, and has received honoraria from AstraZeneca, Eli Lilly, Astellas, Pfizer, Sanofi, Bristol-Myers Squibb, and GlaxoSmithKline. Dr. Sabatine has served on scientific advisory boards for AstraZeneca; has received honoraria for education presentations and served on the Speakers' Bureau for Bristol-Myers Squibb; has received honoraria for education presentations from Eli Lilly; has received research grant support, served on the scientific advisory board, and received honoraria for education presentations from Sanofi-Aventis; and has received research grant support from Schering-Plough. Dr. Steinhubl is currently a full-time employee of The Medicines Company. Dr. Topol is a consultant to Sanofi-Aventis and Daiichi Sankyo. Dr. Berger is a consultant to Accumetrics, The Medicines Company, Eli Lilly/Daiichi Sankyo, and Novartis/Portola (<$10,000/year), and has received research funding from Thrombovision, Helena, Accumetrics, AstraZeneca, Haemoscope, The Medicines Company, Corgenix/Aspirin Works, and Eli Lilly/Daiichi Sankyo.

	References

Top Abstract Methods Results Discussion Conclusions References

 
1. Meadows TA, Bhatt DL. Clinical aspects of platelet inhibitors and thrombus formation Circ Res 2007;100:1261-1275.[Abstract/Free Full Text]

2. Davi G, Patrono C. Platelet activation and atherothrombosis N Engl J Med 2007;357:2482-2494.[CrossRef][Web of Science][Medline]

3. Falk E. Coronary thrombosis: pathogenesis and clinical manifestations Am J Cardiol 1991;68:28B-35B.[CrossRef][Medline]

4. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes N Engl J Med 1992;326:310-318.[Web of Science][Medline]

5. Ruggeri ZM. Platelets in atherothrombosis Nat Med 2002;8:1227-1234.[CrossRef][Web of Science][Medline]

6. Antiplatelet Trialists' Collaboration Collaborative overview of randomised trials of antiplatelet therapy—I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients BMJ 1994;308:81-106.[Abstract/Free Full Text]

7. Antithrombotic Trialists Collaboration Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients BMJ 2002;324:71-86.[Abstract/Free Full Text]

8. Patrono C, Coller B, FitzGerald GA, Hirsh J, Roth G. Platelet-active drugs: the relationships among dose, effectiveness, and side effects: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest 2004;126(Suppl):234S-264S.[Abstract/Free Full Text]

9. Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown DL. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials JAMA 2006;295:306-313.[Abstract/Free Full Text]

10. Boersma E, Harrington RA, Moliterno DJ, et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials Lancet 2002;359:189-198.[CrossRef][Web of Science][Medline]

11. Escolar G, Bastida E, Garrido M, Rodriguez-Gomez J, Castillo R, Ordinas A. Sex-related differences in the effects of aspirin on the interaction of platelets with subendothelium Thromb Res 1986;44:837-847.[CrossRef][Web of Science][Medline]

12. Levin RI. The puzzle of aspirin and sex N Engl J Med 2005;352:1366-1368.[CrossRef][Web of Science][Medline]

13. Iakovou I, Dangas G, Mehran R, et al. Gender differences in clinical outcome after coronary artery stenting with use of glycoprotein IIb/IIIa inhibitors Am J Cardiol 2002;89:976-979.[CrossRef][Web of Science][Medline]

14. CAPRIE Steering Committee A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE) Lancet 1996;348:1329-1339.[CrossRef][Web of Science][Medline]

15. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial Lancet 2004;364:331-337.[CrossRef][Web of Science][Medline]

16. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events N Engl J Med 2006;354:1706-1717.[CrossRef][Web of Science][Medline]

17. Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial Lancet 2005;366:1607-1621.[CrossRef][Web of Science][Medline]

18. Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation N Engl J Med 2005;352:1179-1189.[CrossRef][Web of Science][Medline]

19. Steinhubl SR, Berger PB, Mann 3rd JT, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial JAMA 2002;288:2411-2420.[Abstract/Free Full Text]

20. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation N Engl J Med 2001;345:494-502.[CrossRef][Web of Science][Medline]

21. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non–ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction) J Am Coll Cardiol 2007;50:e1-e157.[Free Full Text]

22. Menon V, Harrington RA, Hochman JS, et al. Thrombolysis and adjunctive therapy in acute myocardial infarction: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest 2004;126(Suppl):549S-575S.[Abstract/Free Full Text]

23. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction) J Am Coll Cardiol 2004;44:671-719.[Free Full Text]

24. Jochmann N, Stangl K, Garbe E, Baumann G, Stangl V. Female-specific aspects in the pharmacotherapy of chronic cardiovascular diseases Eur Heart J 2005;26:1585-1595.[Abstract/Free Full Text]

25. Deeks J, Altman D, Bradburn M. Statistical methods for examining heterogeneity and combining results from several studies in meta-analysisIn: Egger M, Davey Smith G, Altman DG, editors. Systematic Reviews in Health Care: Meta-Analysis in Context. 2nd edition. London: BMJ Publication Group; 2001.

26. Mehta SR, Cannon CP, Fox KA, et al. Routine vs. selective invasive strategies in patients with acute coronary syndromes: a collaborative meta-analysis of randomized trials JAMA 2005;293:2908-2917.[Abstract/Free Full Text]

27. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease J Natl Cancer Inst 1959;22:719-748.[Web of Science][Medline]

28. Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials Progr Cardiovasc Dis 1985;27:335-371.[Web of Science][Medline]

29. Awtry EH, Loscalzo J. Aspirin Circulation 2000;101:1206-1218.[Free Full Text]

30. Helton TJ, Bavry AA, Kumbhani DJ, Duggal S, Roukoz H, Bhatt DL. Incremental effect of clopidogrel on important outcomes in patients with cardiovascular disease: a meta-analysis of randomized trials Am J Cardiovasc Drugs 2007;7:289-297.[CrossRef][Medline]

31. Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women N Engl J Med 2005;352:1293-1304.[CrossRef][Web of Science][Medline]

32. Hershey LA. Stroke prevention in women: role of aspirin versus ticlopidine Am J Med 1991;91:288-292.[CrossRef][Web of Science][Medline]

33. Cho L, Topol EJ, Balog C, et al. Clinical benefit of glycoprotein IIb/IIIa blockade with abciximab is independent of gender: pooled analysis from EPIC, EPILOG and EPISTENT trials. Evaluation of 7E3 for the Prevention of Ischemic Complications. Evaluation in Percutaneous Transluminal Coronary Angioplasty to Improve Long-Term Outcome with Abciximab GP IIb/IIIa blockade. Evaluation of Platelet IIb/IIIa Inhibitor for Stent. J Am Coll Cardiol 2000;36:381-386.[Abstract/Free Full Text]

34. Fernandes LS, Tcheng JE, O'Shea JC, et al. Is glycoprotein IIb/IIIa antagonism as effective in women as in men following percutaneous coronary intervention?. Lessons from the ESPRIT study. J Am Coll Cardiol 2002;40:1085-1091.[Abstract/Free Full Text]

35. Quinn MJ, Fitzgerald DJ. Ticlopidine and clopidogrel Circulation 1999;100:1667-1672.[Abstract/Free Full Text]

36. Maree AO, Fitzgerald DJ. Variable platelet response to aspirin and clopidogrel in atherothrombotic disease Circulation 2007;115:2196-2207.[Free Full Text]

37. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives J Am Coll Cardiol 2007;49:1505-1516.[Abstract/Free Full Text]

38. Eikelboom JW, Hirsh J, Weitz JI, Johnston M, Yi Q, Yusuf S. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events Circulation 2002;105:1650-1655.[Abstract/Free Full Text]

39. Gum PA, Kottke-Marchant K, Welsh PA, White J, Topol EJ. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease J Am Coll Cardiol 2003;41:961-965.[Abstract/Free Full Text]

40. Gurbel PA, Bliden KP, Hiatt BL, O'Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity Circulation 2003;107:2908-2913.[Abstract/Free Full Text]

41. Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction Circulation 2004;109:3171-3175.[Abstract/Free Full Text]

42. Serebruany VL, Steinhubl SR, Berger PB, Malinin AI, Bhatt DL, Topol EJ. Variability in platelet responsiveness to clopidogrel among 544 individuals J Am Coll Cardiol 2005;45:246-251.[Abstract/Free Full Text]

43. Chen WH, Lee PY, Ng W, Tse HF, Lau CP. Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite clopidogrel pretreatment J Am Coll Cardiol 2004;43:1122-1126.[Abstract/Free Full Text]

44. Dorsch MP, Lee JS, Lynch DR, et al. Aspirin resistance in patients with stable coronary artery disease with and without a history of myocardial infarction Ann Pharmacother 2007;41:737-741.[Abstract/Free Full Text]

45. Helgason CM, Bolin KM, Hoff JA, et al. Development of aspirin resistance in persons with previous ischemic stroke Stroke 1994;25:2331-2336.[Abstract/Free Full Text]

46. Moscucci M, Fox KA, Cannon CP, et al. Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE) Eur Heart J 2003;24:1815-1823.[Abstract/Free Full Text]

47. Alexander KP, Chen AY, Newby LK, et al. Sex differences in major bleeding with glycoprotein IIb/IIIa inhibitors: results from the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) initiative Circulation 2006;114:1380-1387.[Abstract/Free Full Text]

48. Alexander KP, Chen AY, Roe MT, et al. Excess dosing of antiplatelet and antithrombin agents in the treatment of non–ST-segment elevation acute coronary syndromes JAMA 2005;294:3108-3116.[Abstract/Free Full Text]

49. Walker AM, Jick H. Predictors of bleeding during heparin therapy JAMA 1980;244:1209-1212.[Abstract/Free Full Text]

50. Rao SV, O'Grady K, Pieper KS, et al. Impact of bleeding severity on clinical outcomes among patients with acute coronary syndromes Am J Cardiol 2005;96:1200-1206.[CrossRef][Web of Science][Medline]

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